1. Apoptosis
Regulation of cell number is determined by a balance between cell proliferation and cell death. One general mechanism of cell death seen in the process of development, differentiation, and cell turnover is apoptosis. Apoptosis is a characteristic form of cell death involving activation of one or more internally controlled pathways leading to autodigestion. Characteristic changes typical of a cell undergoing apoptosis include cell shrinkage and loss of contact with neighboring cells, cytoskeletal disruption, membrane blebbing and alterations in the plasma membrane, and endonuclease activity-associated degradation of DNA. There are various inducers of apoptosis including: physiologic activators such as TNF, Fas ligand, transforming growth factor .beta., certain neurotransmitters, calcium, and glucocorticoids; damage-related inducers such as heat shock, viral infection, bacterial toxins, tumor suppressors, and free radicals; therapeutic agents such as chemotherapeutic agents (cisplatin, doxorubicin, bleomycin, etc.), and gamma radiation; and toxins such as .beta.-amyloid peptide.
Apoptosis can be induced by the binding and cross-linking of a cell surface receptor known as Fas. Human Fas (also known as APO-1 and CD95) is a cell surface protein consisting of 325 amino acids with a signal sequence at the NH.sub.2 -terminus and a membrane spanning region in the middle of the molecule. Fas appears to be constitutively expressed on cells of a varied, but limited, number of normal tissues, including skeletal muscle, liver, skin, heart, lung, kidney, and reproductive tissues (Leithauser et al., 1993, Laboratory Invest. 69:415; Watanabe-Fukunaga et al., 1992, J. Immunol., 148:1274). Malignant cells of hematologic or nonhematologic origin have been analyzed for Fas expression (See, e.g., Leithauser et al., 1993, supra). Of relevance to the present invention, for example, a minority (approximately 15%) of B cell chronic lymphocytic leukemia cells (CLL) express the Fas antigen (Panayiotidis et al., 1995, Leukemia 9:1227-32); only one of eight B-cell lymphomas expressed Fas antigen which was at a very low level (Owen-Schaub et al., 1993, J. Inmmunother. 14:234-41); and only one of eight Burkitt's lymphoma expressed Fas antigen (Leithauser et al., 1993, supra).
Fas-mediated apoptosis requires cross-linking of Fas with either agonistic anti-Fas antibody, with cell bound FasL (Fas-ligand), or with soluble FasL (see, e.g. Alderson et al., 1995, J. Exp. Med. 181:71-77; Yonehara et al., 1989, J. Exp. Med. 169:1747-1756; Suda et al., 1994, J. Exp. Med. 179:873). However, the response to Fas cross-linking on Fas-bearing cells is variable. For example, resistance to Fas-mediated apoptosis after anti-Fas antibody treatment has been observed in some myeloma cells (Westendorf et al., 1995, Blood 85:3566-76), B-cell and T-cell lymphomas (Owen-Schaub et al., 1993, supra), and CLL (Panayiotidis et al., 1995, supra). Thus, the fact that a cell may bear Fas antigen does not necessarily confer sensitivity of that cell to anti-Fas mediated cytotoxicity.
2. Primary Central Nervous System Lymphomas (PCNSL)
PCNSL, an intracranial malignant lymphoma, involves the brain parenchyma, meninges, and rarely, the eye. While occurrence of PCNSL was relatively uncommon, the incidence of PCNSL continues to rise among patients afflicted with AIDS, and among patients receiving allogenic solid organ or bone marrow transplantation. For example, it is estimated that 2% to 6% of AIDS patients will develop clinical evidence of PCNSL; and that at autopsy, up to 11% will have occult PCNSL (Schultz et al., 1996, J. Clin. Oncol. 14:556-564). An intrinsic feature of PCNSL is resistance to standard therapeutic regimens. Radiation therapy, the primary therapy currently used, typically results in a high failure rate; and radiation combined with chemotherapy (cyclophosphamide, doxorubicin, vincristine, and dexamethasone) does not significantly improve survival amongst treated patients (Schultz et al., 1996, supra). Lack of an effective therapy contributes towards the poor prognosis of patients with this malignancy. In that regard, life expectancy of an immuno-suppressed patient having PCNSL is approximately 2 to 4 months (Schultz et al., 1996, supra).
Hence, a need still exists for a method to treat PCNSL with better therapeutic efficacy than the current standard treatment, and with minimal toxicity.